GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

Salvatore Rizza; Luca Di Leo; Chiara Pecorari; Paola Giglio; Fiorella Faienza; Costanza Montagna; Emiliano Maiani; Michele Puglia; Francesca M Bosisio; Trine Skov Petersen; Lin Lin; Vendela Rissler; Juan Salamanca Viloria; Yonglun Luo; Elena Papaleo; Daniela De Zio; Blagoy Blagoev; Giuseppe Filomeni

doi:10.1016/j.celrep.2023.111997

GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

Salvatore Rizza, Luca Di Leo, Chiara Pecorari, Paola Giglio, Fiorella Faienza, Costanza Montagna, Emiliano Maiani, Michele Puglia, Francesca M Bosisio, Trine Skov Petersen, Lin Lin, Vendela Rissler, Juan Salamanca Viloria, Yonglun Luo, Elena Papaleo, Daniela De Zio, Blagoy Blagoev, Giuseppe Filomeni

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

7 Citationer (Scopus)

Abstract

Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.

Originalsprog	Engelsk
Artikelnummer	111997
Tidsskrift	Cell Reports
Vol/bind	42
Nummer	1
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2023.111997
Status	Udgivet - 31 jan. 2023

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10.1016/j.celrep.2023.111997Licens: CC BY

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Rizza, S., Di Leo, L., Pecorari, C., Giglio, P., Faienza, F., Montagna, C., Maiani, E., Puglia, M., Bosisio, F. M., Petersen, T. S., Lin, L., Rissler, V., Viloria, J. S., Luo, Y., Papaleo, E., De Zio, D., Blagoev, B., & Filomeni, G. (2023). GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation. Cell Reports, 42(1), Artikel 111997. https://doi.org/10.1016/j.celrep.2023.111997

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title = "GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation",

abstract = "Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.",

keywords = "CP: Cancer, CP: Molecular biology, FAK inhibitors, S-nitrosylation, SRC, anoikis, cancer, focal adhesion, nitric oxide, spheroids, Focal Adhesion Kinase 1/genetics, Phosphorylation, Aldehyde Oxidoreductases/metabolism, Humans, Tumor Microenvironment, Alcohol Dehydrogenase/metabolism, Neoplasms/genetics, Nitric Oxide/metabolism, Protein Processing, Post-Translational",

author = "Salvatore Rizza and {Di Leo}, Luca and Chiara Pecorari and Paola Giglio and Fiorella Faienza and Costanza Montagna and Emiliano Maiani and Michele Puglia and Bosisio, {Francesca M} and Petersen, {Trine Skov} and Lin Lin and Vendela Rissler and Viloria, {Juan Salamanca} and Yonglun Luo and Elena Papaleo and {De Zio}, Daniela and Blagoy Blagoev and Giuseppe Filomeni",

year = "2023",

month = jan,

day = "31",

doi = "10.1016/j.celrep.2023.111997",

language = "English",

volume = "42",

journal = "Cell Reports",

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T1 - GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

AU - Rizza, Salvatore

AU - Di Leo, Luca

AU - Pecorari, Chiara

AU - Giglio, Paola

AU - Faienza, Fiorella

AU - Montagna, Costanza

AU - Maiani, Emiliano

AU - Puglia, Michele

AU - Bosisio, Francesca M

AU - Petersen, Trine Skov

AU - Lin, Lin

AU - Rissler, Vendela

AU - Viloria, Juan Salamanca

AU - Luo, Yonglun

AU - Papaleo, Elena

AU - De Zio, Daniela

AU - Blagoev, Blagoy

AU - Filomeni, Giuseppe

PY - 2023/1/31

Y1 - 2023/1/31

N2 - Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.

AB - Nitric oxide (NO) production in the tumor microenvironment is a common element in cancer. S-nitrosylation, the post-translational modification of cysteines by NO, is emerging as a key transduction mechanism sustaining tumorigenesis. However, most oncoproteins that are regulated by S-nitrosylation are still unknown. Here we show that S-nitrosoglutathione reductase (GSNOR), the enzyme that deactivates S-nitrosylation, is hypo-expressed in several human malignancies. Using multiple tumor models, we demonstrate that GSNOR deficiency induces S-nitrosylation of focal adhesion kinase 1 (FAK1) at C658. This event enhances FAK1 autophosphorylation and sustains tumorigenicity by providing cancer cells with the ability to survive in suspension (evade anoikis). In line with these results, GSNOR-deficient tumor models are highly susceptible to treatment with FAK1 inhibitors. Altogether, our findings advance our understanding of the oncogenic role of S-nitrosylation, define GSNOR as a tumor suppressor, and point to GSNOR hypo-expression as a therapeutically exploitable vulnerability in cancer.

KW - CP: Cancer

KW - CP: Molecular biology

KW - FAK inhibitors

KW - S-nitrosylation

KW - SRC

KW - anoikis

KW - cancer

KW - focal adhesion

KW - nitric oxide

KW - spheroids

KW - Focal Adhesion Kinase 1/genetics

KW - Phosphorylation

KW - Aldehyde Oxidoreductases/metabolism

KW - Humans

KW - Tumor Microenvironment

KW - Alcohol Dehydrogenase/metabolism

KW - Neoplasms/genetics

KW - Nitric Oxide/metabolism

KW - Protein Processing, Post-Translational

UR - http://www.scopus.com/inward/record.url?scp=85146449432&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2023.111997

DO - 10.1016/j.celrep.2023.111997

M3 - Journal article

C2 - 36656716

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 111997

ER -

GSNOR deficiency promotes tumor growth via FAK1 S-nitrosylation

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